Scar formation remains an important clinical problem for which inadequate treatment is available. Clinical observation and experimental studies support the idea that mucosa heals more rapidly and with less scarring than skin. These observations strongly suggest that 1) adults maintain the capacity to heal with minimal scar, and 2) adult skin healing can be manipulated to reduce scar formation. At present, the mechanisms responsible for the improved repair of adult mucosa are poorly defined. Elements that might be the key to privileged mucosal repair include the innate epithelial response, the fibroblast/connective tissue response, and reciprocal dynamic interactions between the epithelial and subepithelial compartments. To date, the concept that epithelial-subepithelial interactions might guide healing and scarring outcomes has received little experimental attention. The hypothesis of this application is that epithelial-connective tissue interactions play a critical role in dictating scar formation, and that these interactions differ in skin and mucosa. The immediate goal of this research is to identify elements that are uniquely produced in epithelium and subepithelial tissue of mucosal versus skin wounds. The research plan will take advantage of three models systems of paired mucosal and skin repair that we have developed in mice (LAD), humans (PTM) and rabbits (TAM). Aim 1 will utilize proteomic and genomic analyses to identify factors that are differently expressed in mucosal and skin wound sites. Factors produced in epithelial and connective tissue compartments will be identified by follow-up localization analysis. This Aim will utilize the newly developed Chicago Biomedical Consortium for the Proteomics/Bioinformatics Project (located at U. Illinois), as well as genomic analysis facilities elsewhere to provide a novel comprehensive analysis of how the response to injury differs in skin and mucosa. Aim 2 will employ in vitro assays to assess the ability of target molecules identified in Aim 1 to modulate cellular functions related to scar formation and healing, including collagen synthesis and myofibroblast formation. Aim 3 will determine if target factors can reduce scar formation in an in vivo preclinical model of hypertrophic scar formation. The long-term goal of the project is to develop an innovative Research Center that will focus on identifying and understanding novel factors that modulate scarring, with a goal of developing useful therapeutic strategies to reduce scar formation in adults.